© 1991 S. Karger AG. Basel 0025-7931/91/0586-0241 $ 2.75/0
Respiration 1991;58:241-248
Control of Breathing in Patients with Chronic Pulmonary Obstructive Disease: Response to Bamiphylline A. Spinellia,A. Fanellib, M. Gorinr', A. Sannab, C. François G. Scanob c,
” Centro Pro Juventute Don C. Gnocchi, Pozzolatico; h Clinica Medica III. Universitédi Firenze; c Servizio di Pronto Soccorso USL HIDCarcggi, Firenze, Italia
Key Words. Chronic obstructive pulmonary disease • Control of breathing • Electromyography • Bamiphylline Abstract. In two groups (A and B) of patients with severe chronic obstructive pulmonary disease (COPD). matched for age and routine pulmonary function testing, we evaluated inspiratory muscle strength (MIP), breathing pattern, mouth occlusion pressure (P,u), inspiratory neural drive, assessed in terms of electromyo graphic activity of both diaphragm (EMGd) and intercostal (EMGint) muscles, and P()1/EMGd ratio, an index of inspiratory neuromuscular coupling. Group A (8 patients) was studied before and after a 7-day period of a new oral xanthine derivative (bamiphylline, 1.2 g daily), and group B (7 patients) was given a placebo. Under control conditions, compared with an age-matched normal control group, groups A and B both exhibited a de crease in MIP, more rapid (increase in respiratory frequency RF) and shallower (decrease in tidal volume; VT) breathing (RSB), a marked increase in both EMGd and EMGint and a lower P,u/EMGd ratio. With bamiphyl line FEV) and P a 0 2 significantly increased, while a substantial increase in MIP was found in 5 out of the 8 pa tients. VT and inspiratory time (T|) also significantly increased, and RF decreased. Both EMGd and EMGint significantly decreased, whereas Plu/EMGd exhibited a substantial increase in 5 out of the 8 patients. Con versely, no significant changes were observed in group B during the study period. From these data we conclude that in patients with COPD, clinical manifestations, probably associated with inspiratory muscle overloading (decrease in muscle strength, RSB, increase in respiratory neural drive, and derangement in neuromuscular coupling) may benefit from a short-term treatment with bamiphylline.
Several lines of evidence suggest that in hypoxic hypercapnic patients with chronic obstructive pulmo nary disease (COPD), oral theophylline may improve ventilatory muscle performance [1|. Such an effect has not been observed in slightly hypoxic, normocapnic COPD patients with cither intravenous theophylline [2] or short-term oral sustained-release theophylline administration [3]. Even though the reasons for these discrepancies are complex, it is not unlikely that the magnitude of hypoxia may play a role [4], Recent clinical methods allow the assessment of the control of breathing at multiple levels: ‘central' (spinal), muscular, and ventilatory [2, 5-12], In pa tients with chronic pulmonary disorders we have re cently shown the possibility of evaluating the control
of breathing by using relatively simple, inexpensive, non-invasive methods [2, 5-7, 11, 12]. Based upon our previous observations [2], the pre sent investigation was aimed at evaluating whether and how a 7-day period of a new oral xanthine deriv ative (bamiphylline) modifies the control of breathing in hyperinflated COPD patients with overloaded ven tilatory muscles.
Subjects and Methods Subjects Fifteen male patients were hospitalized to assess the nature and the extent of their complaints. They were studied after the na ture of the experimental technique and the purpose of the in vestigation had been fully explained to them. Only patients with no recent history of theophylline administration were included.
Downloaded by: Stockholm University Library 130.237.165.40 - 12/4/2018 3:49:16 PM
Introduction
242
Functional Evaluation Routine spirometry and arterial blood gas samples obtained with subjects in a seated position were measured as previously de scribed [12J. The normal values for lung volumes are those pro posed by the European Community for Coal and Steel [14]. Maxi mal static inspiratory pressure (MIP) at functional residual capac ity (FRC) against an obstructed mouthpiece, with a small leak to minimize oral pressure artifacts, was measured using a differential pressure transducer (Statham SC 1001). Subjects performed maxi mal inspiratory efforts and were instructed to maintain maximal pressures for at least 1 s. The mean of three reproducible and sat isfactory measurements was calculated. After baseline routine testing during room-air breathing, the ventilatory pattern, respiratory drive and mouth occlusion pres sure were evaluated with the subjects in a comfortable supine po sition, wearing a noseclip and breathing through a mouthpiece. In the apparatus used, the inspiratory line was separated from the ex piratory one by a one-way valve (Hans-Rudolph) connected to a Flcisch type 3 pneumotachograph. The flow signal was integrated into volume. From the spirogram we derived, breath by breath, time and volume components of the respiratory cycle: inspiratory time (Tj), expiratory time (Tc), total time of the respiratory cycle (Tlol), and tidal volume (VT). Mean inspiratory flow (VT/Tj). duty cycle (T;/Tu,t), respiratory frequency (RF = 1/Tlotx60) and instan taneous ventilation (VE = VTx RF) were also calculated. Mouth pressure during tidal breathing (VT) maneuvres was measured using a pressure transducer (Statham P23ID). Mouth occlusion pressure 0.1 s after the beginning of inspiration (P,M) was recorded as previously described [2, 5-7, 11. 12]. Expired CO, (PctCO,) was sampled continuously at the mouth by an infrared CO, meter. The values for dead space and resistance of the system up to a flow of 4 I • s"1were 178 ml and 0.09 kPa • l"1• s, respectively. The electromyographic activity (EMC) of the respiratory mus cles was recorded as previously described [2, 6, 7,11,12], The EMG of the chest wall muscles was recorded from the second para sternal intercostal (EMGint). and diaphragm (EMGd) muscles via large surface electrodes. The EMGd was recorded from the lower anterolateral rib cage as described by Gross et al. [15]. Muscle action potentials (‘raw’) were differentially amplified, filtered between 100 and 1,000 Hz, to remove as much ECG as pos sible, without significantly filtering EMG. The filtered EMG sig nal along with mouth pressure recording were displayed on a sin gle-beam storage oscilloscope (Tektronix 5115). EMG activity was full-wave rectified and integrated over time (time constant 150 ms) using a third-order, low-pass filter to provide a measurement of change in average electrical activity as a function of time, re ferred to as ’moving time average' (X) [8, 9], Inspiratory activity was quantified both as peak of activity and as rate of rise of activ ity (slope). The former was directly measured in arbitrary units (XP) and the latter was obtained by dividing XP by the inspiratory time (XP/Tj).
Owing to the variability of the impedance between diaphragm and electrodes, absolute values (mV) are not comparable among different subjects. To overcome this problem and to obtain a ref erence value, EMG activity was measured while the subject, con nected to the pneumotachograph, performed an inspiratory ca pacity (IC) maneuvre breathing in up to total lung capacity (TLC). This maneuvre was repeated at least three times, and in each sub ject both IC and the intensity of the recorded diaphragmatic EMG were closely reproducible (less than 5% variability). The mean level of this EMG activity was taken as a reference: all the succes sive measurements have been expressed as a percentage of this reference value obtained at TLC. As EMG activity of an inspirato ry muscle may include cardiac muscle activity, we checked cardiac artifacts to manually gate ECG. when necessary, so that it would not contribute to the EMG. The output of C 0 2 meter, the flow signal, the integrated flow signal, the mouth pressure, and the moving time average were re corded continuously on a multichannel chart recorder. After a 10min adaptation period, which allowed the patient to equilibrate with the circuit as shown by the stability of the CO, trace, baseline evaluation began. Respiratory cycles, occlusions and EMG were continuously recorded over a 10 min time period and the cycles following occlusions discarded. Average values for each subject are presented. Protocol After baseline function testing, patients were randomly as signed to either study goup A (8 patients) or control group B (7 patients). Group A was administered a 7-day course of an oral theophylline derivative (bamiphylline; a gift from Alfa Wasscrmann Italy). The drug was given in two doses of 600 mg each: at 8 a.m. and 8 p. m. daily. Group B received a placebo. At the conclusion of the study period, pulmonary function test ing was repeated in all patients. In group A, testing was carried out 2 h after the last morning intake of the drug when blood sam ples were also obtained to measure bamiphylline plasma levels by chromatography [16,17]. As the plasma levels of bamiphylline had to be measured after 7 days to ensure that the therapeutic level was attained, the study was carried out in single blind. Recording and processing of the data was done by one of us (A.S.) who was unaware of whether the patients had received the drug or placebo. Results were compared by the Wilcoxon test for paired sam ples and the Mann-Whitney U test for unpaired samples, and p
Respiration 1991;58:241-248
Control of Breathing in Patients with Chronic Pulmonary Obstructive Disease: Response to Bamiphylline A. Spinellia,A. Fanellib, M. Gorinr', A. Sannab, C. François G. Scanob c,
” Centro Pro Juventute Don C. Gnocchi, Pozzolatico; h Clinica Medica III. Universitédi Firenze; c Servizio di Pronto Soccorso USL HIDCarcggi, Firenze, Italia
Key Words. Chronic obstructive pulmonary disease • Control of breathing • Electromyography • Bamiphylline Abstract. In two groups (A and B) of patients with severe chronic obstructive pulmonary disease (COPD). matched for age and routine pulmonary function testing, we evaluated inspiratory muscle strength (MIP), breathing pattern, mouth occlusion pressure (P,u), inspiratory neural drive, assessed in terms of electromyo graphic activity of both diaphragm (EMGd) and intercostal (EMGint) muscles, and P()1/EMGd ratio, an index of inspiratory neuromuscular coupling. Group A (8 patients) was studied before and after a 7-day period of a new oral xanthine derivative (bamiphylline, 1.2 g daily), and group B (7 patients) was given a placebo. Under control conditions, compared with an age-matched normal control group, groups A and B both exhibited a de crease in MIP, more rapid (increase in respiratory frequency RF) and shallower (decrease in tidal volume; VT) breathing (RSB), a marked increase in both EMGd and EMGint and a lower P,u/EMGd ratio. With bamiphyl line FEV) and P a 0 2 significantly increased, while a substantial increase in MIP was found in 5 out of the 8 pa tients. VT and inspiratory time (T|) also significantly increased, and RF decreased. Both EMGd and EMGint significantly decreased, whereas Plu/EMGd exhibited a substantial increase in 5 out of the 8 patients. Con versely, no significant changes were observed in group B during the study period. From these data we conclude that in patients with COPD, clinical manifestations, probably associated with inspiratory muscle overloading (decrease in muscle strength, RSB, increase in respiratory neural drive, and derangement in neuromuscular coupling) may benefit from a short-term treatment with bamiphylline.
Several lines of evidence suggest that in hypoxic hypercapnic patients with chronic obstructive pulmo nary disease (COPD), oral theophylline may improve ventilatory muscle performance [1|. Such an effect has not been observed in slightly hypoxic, normocapnic COPD patients with cither intravenous theophylline [2] or short-term oral sustained-release theophylline administration [3]. Even though the reasons for these discrepancies are complex, it is not unlikely that the magnitude of hypoxia may play a role [4], Recent clinical methods allow the assessment of the control of breathing at multiple levels: ‘central' (spinal), muscular, and ventilatory [2, 5-12], In pa tients with chronic pulmonary disorders we have re cently shown the possibility of evaluating the control
of breathing by using relatively simple, inexpensive, non-invasive methods [2, 5-7, 11, 12]. Based upon our previous observations [2], the pre sent investigation was aimed at evaluating whether and how a 7-day period of a new oral xanthine deriv ative (bamiphylline) modifies the control of breathing in hyperinflated COPD patients with overloaded ven tilatory muscles.
Subjects and Methods Subjects Fifteen male patients were hospitalized to assess the nature and the extent of their complaints. They were studied after the na ture of the experimental technique and the purpose of the in vestigation had been fully explained to them. Only patients with no recent history of theophylline administration were included.
Downloaded by: Stockholm University Library 130.237.165.40 - 12/4/2018 3:49:16 PM
Introduction
242
Functional Evaluation Routine spirometry and arterial blood gas samples obtained with subjects in a seated position were measured as previously de scribed [12J. The normal values for lung volumes are those pro posed by the European Community for Coal and Steel [14]. Maxi mal static inspiratory pressure (MIP) at functional residual capac ity (FRC) against an obstructed mouthpiece, with a small leak to minimize oral pressure artifacts, was measured using a differential pressure transducer (Statham SC 1001). Subjects performed maxi mal inspiratory efforts and were instructed to maintain maximal pressures for at least 1 s. The mean of three reproducible and sat isfactory measurements was calculated. After baseline routine testing during room-air breathing, the ventilatory pattern, respiratory drive and mouth occlusion pres sure were evaluated with the subjects in a comfortable supine po sition, wearing a noseclip and breathing through a mouthpiece. In the apparatus used, the inspiratory line was separated from the ex piratory one by a one-way valve (Hans-Rudolph) connected to a Flcisch type 3 pneumotachograph. The flow signal was integrated into volume. From the spirogram we derived, breath by breath, time and volume components of the respiratory cycle: inspiratory time (Tj), expiratory time (Tc), total time of the respiratory cycle (Tlol), and tidal volume (VT). Mean inspiratory flow (VT/Tj). duty cycle (T;/Tu,t), respiratory frequency (RF = 1/Tlotx60) and instan taneous ventilation (VE = VTx RF) were also calculated. Mouth pressure during tidal breathing (VT) maneuvres was measured using a pressure transducer (Statham P23ID). Mouth occlusion pressure 0.1 s after the beginning of inspiration (P,M) was recorded as previously described [2, 5-7, 11. 12]. Expired CO, (PctCO,) was sampled continuously at the mouth by an infrared CO, meter. The values for dead space and resistance of the system up to a flow of 4 I • s"1were 178 ml and 0.09 kPa • l"1• s, respectively. The electromyographic activity (EMC) of the respiratory mus cles was recorded as previously described [2, 6, 7,11,12], The EMG of the chest wall muscles was recorded from the second para sternal intercostal (EMGint). and diaphragm (EMGd) muscles via large surface electrodes. The EMGd was recorded from the lower anterolateral rib cage as described by Gross et al. [15]. Muscle action potentials (‘raw’) were differentially amplified, filtered between 100 and 1,000 Hz, to remove as much ECG as pos sible, without significantly filtering EMG. The filtered EMG sig nal along with mouth pressure recording were displayed on a sin gle-beam storage oscilloscope (Tektronix 5115). EMG activity was full-wave rectified and integrated over time (time constant 150 ms) using a third-order, low-pass filter to provide a measurement of change in average electrical activity as a function of time, re ferred to as ’moving time average' (X) [8, 9], Inspiratory activity was quantified both as peak of activity and as rate of rise of activ ity (slope). The former was directly measured in arbitrary units (XP) and the latter was obtained by dividing XP by the inspiratory time (XP/Tj).
Owing to the variability of the impedance between diaphragm and electrodes, absolute values (mV) are not comparable among different subjects. To overcome this problem and to obtain a ref erence value, EMG activity was measured while the subject, con nected to the pneumotachograph, performed an inspiratory ca pacity (IC) maneuvre breathing in up to total lung capacity (TLC). This maneuvre was repeated at least three times, and in each sub ject both IC and the intensity of the recorded diaphragmatic EMG were closely reproducible (less than 5% variability). The mean level of this EMG activity was taken as a reference: all the succes sive measurements have been expressed as a percentage of this reference value obtained at TLC. As EMG activity of an inspirato ry muscle may include cardiac muscle activity, we checked cardiac artifacts to manually gate ECG. when necessary, so that it would not contribute to the EMG. The output of C 0 2 meter, the flow signal, the integrated flow signal, the mouth pressure, and the moving time average were re corded continuously on a multichannel chart recorder. After a 10min adaptation period, which allowed the patient to equilibrate with the circuit as shown by the stability of the CO, trace, baseline evaluation began. Respiratory cycles, occlusions and EMG were continuously recorded over a 10 min time period and the cycles following occlusions discarded. Average values for each subject are presented. Protocol After baseline function testing, patients were randomly as signed to either study goup A (8 patients) or control group B (7 patients). Group A was administered a 7-day course of an oral theophylline derivative (bamiphylline; a gift from Alfa Wasscrmann Italy). The drug was given in two doses of 600 mg each: at 8 a.m. and 8 p. m. daily. Group B received a placebo. At the conclusion of the study period, pulmonary function test ing was repeated in all patients. In group A, testing was carried out 2 h after the last morning intake of the drug when blood sam ples were also obtained to measure bamiphylline plasma levels by chromatography [16,17]. As the plasma levels of bamiphylline had to be measured after 7 days to ensure that the therapeutic level was attained, the study was carried out in single blind. Recording and processing of the data was done by one of us (A.S.) who was unaware of whether the patients had received the drug or placebo. Results were compared by the Wilcoxon test for paired sam ples and the Mann-Whitney U test for unpaired samples, and p
